The intrinsic apoptosis pathway involves the disruption of mitochondria and the releases of mitochondrial proteins, leading to the activation of caspase-9 and a downstream caspase cascade. Although cell death can still proceed in the absence of caspase-9, it was delayed in casapse-9-deficient B cells with significant induction of autophagy. Experiments are proposed to test the hypothesis that the interplay between caspase-9 and autophagy plays an important role in regulating programmed cell death. Autophagy may help to protect against cell death by clearing damaged mitochondria: 1) To study the mechanisms for the rescue of caspase-9-deficient B cells after partial loss of mitochondrial membrane potential; 2) To determine the mechanisms by which autophagy promotes the survival of B cells; and 3) To investigate the roles of caspase-9 and autophagy in the regulation of development and functions of lymphocytes in vivo. The interplays between caspase signaling and mitochondrial autophagy in regulating programmed cell death will be investigated. The proposed study will help to gain insights into the molecular mechanisms for the regulation of mitochondrial autophagy during cell death. Mitochondrial quality control by autophagy has been suggested to play essential roles in the prevention against aging, cancer and neurodegenerative diseases. The proposed study may facilitate the development of better strategies for treating diseases involving abnormal mitochondrial autophagy. PUBLIC HEALTH RELEVANCE: This project seeks to investigate the regulation of programmed cell death by caspases and autophagy.